PKPD Modeling of Biomarkers in the Early Phase of Drug Development Colburn

There are numerous stages along the development cycle where the development of biomarkers and PK/PD modeling can add value. Incorporation of PK/ PD studies throughout preclinical and clinical development may lead to earlier identification of optimal dosing regimens in clinical development and may reduce the overall time of drug development. Beyond the traditional paradigm of using fractions of the nonclinical toxic doses in animals to design first- in -human dosing schedules, the use of PK/PD modeling in early preclinical development allows one to define more precisely the dose-concentration-pharmacological effects and dose-concentration-toxicity relationships with the use of key efficacy and safety biomarkers. The extrapolation of these results to humans using a combination of in vitro and in vivo data can be particularly helpful in determining the appropriate dosing regimen for phase I studies and in guiding dose escalation in order to achieve the systemic exposure in humans that is expected to be associated with the desired effect on the biomarker and ultimately, the clinical outcome. Overall, the use of validated biomarkers and the application of PK/PD modeling and simulation principles represent an opportunity to identify optimal drug candidates and possibly to develop drugs in the shortest time frame possible [7-9].

PK/PD modeling output can be no better than the biomarkers or surrogate endpoints used for the modeling (i.e., the input). As we increase our understanding of biomarkers, surrogate markers, and disease and drug mechanisms, PK/PD modeling inputs and outputs will improve and, consequently, predictive power will improve.

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Project Management Made Easy

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